1. Field of the Invention
The present invention relates to a structure comprising a porous body, a capping member, and a connecting member for connecting the porous body and the capping member, and relates also to a method for releasing a substance kept by the capping member in the porous body.
2. Related Background Art
Many investigations are being made on stimulation-responsive materials which function by changing a shape or a property thereof in response to an external stimulation such as light irradiation, electric field application, and chemical substance addition; or an environmental change such as a temperature change, and a pH change. The function of the stimulation-responsive material can be controlled from outside by utilizing the property, and is promising in various application fields, such as drug delivery.
Generally, a drug is dosed into a body by injection, oral administration, painting, or a like method, and the dosed drug circulates in the body to reach a target site. In these dosing method generally, the drug can diffuse to a portion other than the targeted diseased portion or may be absorbed or decomposed in a digestive tract or other tract undesirably, reaching the diseased portion finally in a quantity (concentration) much smaller than the dosed quantity. Therefore, the drug is dosed in a quantity larger than that actually required.
To solve the above problem, various measures are taken, including modification of a portion of the drug compound relating to the absorption or decomposition without lowering the drug effect, use of a drug carrier, and so forth. The drug carrier carries a drug selectively to a targeted diseased portion or an objective matter such as internal organs, tissues, cells, and pathogens. This technique employing a drug carrier is called a drug delivery system (hereinafter referred to as “DDS”). This DDS technique can increase the treatment effect of the drug, and can decrease the drug dose to lower the adverse effect of the drug advantageously. As the drug carrier, liposomes, lipid microsheres, and the like are being investigated.
A liposome is a spherical vesicle of lipid having a hydrophilic portion and a hydrophobic portion, constituted of a bilayer with the hydrophobic groups placed inside to be stable to an outside water environment. A liposome having a stable bilayer structure can be formed by dissolving a natural lipid such as lecithin and cholesterol in an organic solvent and dispersing it in water by ultrasonic treatment or a like method. In the liposome forming process, a drug to be carried can be enclosed in the liposome, A drug which is a hydrophobic substance is held in the inside of the bilayer whereas a drug which is hydrophilic is held in the inside water phase enclosed by the bilayer.
Lipid microspheres can be prepared by suspending a drug-containing soybean oil and lecithin in water, having the lecithin on the surface and the drug-containing soybean oil enclosed therein. Medical formulations comprising such lipid microspheres enclosing an anti-inflammatory drug are used in clinical treatment. Japanese Patent Application Laid-Open No. H05-221852 discloses a method for forming lipid microspheres containing a fatty acid ester and having fine particle surfaces by dissolving a fat-soluble anticancer agent in the fatty acid and homogenizing the fatty acid ester solution with a surfactant such as a phospholipids. However, the liposome structure can readily be destroyed by contact with a lipid or protein in blood, being not stable in vivo for a long time. For stabilization, modification of the liposome by polyethylene glycol (PEG) or a polysaccharide is investigated. However, the stability is not satisfactory yet. Further, to use the lipid microsphere, the drug should be fat-soluble, but fat-soluble drug is not stable in the blood similarly as the liposome, and is liable to migrate to reticuloendothelial system. The liposome needs to be improved more for use as the drug carrier.
For improving the stability of the aforementioned drug carriers in the blood, a report is presented which utilizes a block copolymer constituted of polyethylene glycol as the hydrophilic portion and polyamino acid as the hydrophobic portion to form a micelle-like structure in an aqueous solution or a phosphate buffer solution (Drug Delivery System, Vol. 6(2), pp77, 1991). This block copolymer is capable of forming a micelle-like stable structure in an aqueous solution or an aqueous phosphate buffer solution. A drug like an anti-cancer agent is enclosed in this structure for stabilization in the blood.
U.S. Pat. No. 3,854,480 discloses a drug delivery system which releases a drug at a controlled rate for a long term. This system employs a structure constituted of a film and a drug-containing core, the film being composed of a polymer such as polyethylene and an ethylene-vinyl acetate copolymer, and the drug-containing core being composed of a matrix of polymethylsiloxane or the like containing a drug dispersed therein. The drug is released to outside from the core through the film by diffusion.
The above disclosures do not teach a technique for releasing the drug selectively to the targeted diseased portion. For more effective medical treatment and lower side effect of the drug, a drug carrier is demanded to be developed which has capability of controlling the drug release at a targeted site as well as the stability after administration in the blood and other portion of the body and on the body surface.
To meet such demand, a technique is disclosed which encloses a drug or a chemical compound in a silica type porous material stable in the body fluid like blood and releases the compound with control by outside stimulation (J. Am. Chem. Soc., Vol. 125, pp4451, 2003). In the disclosed technique, the material for enclosing the drug is mesoporous silica (MCM-41) having an average particle size of 200 nm, and an average pore diameter of 2.3 nm (hereinafter referred to as a “silica structure”) modified by 2-(propyldisulfanyl)ethylamine. By this technique, the silica structure is immersed in an aqueous solution of ATP and vancomycin, and thereto CdS (average particle size: 2.0 nm) is added which has been modified by acetic acid thiol to cause bridging by chemical bonding between the amino groups on the surface of the silica structure and the carboxyl groups of the CdS surface to cap the silica structure to enclose the drug. The compound enclosed in the silica structure is released by treatment with a reducing agent such as DTT and mercaptoethanol to cleave the S—S bond of the disulfanyl groups to remove the CdS from the mesoporous silica.
A report (J. Material. Biomed. Mater. Res. 51, pp293 (2000)) discloses a technique for destroying nano particles constituted of cores of a hydrogel of an N-isopropylacrylamide-acrylamide copolymer (NIPAAm-AAm) coated with gold by swelling of the NIPAAm-AAm core by absorption of near infrared light of 800 to 1200 nm and a resulting photothermal conversion reaction. This report suggests also possibility of drug release, by light response, from NIPAAm-AAm containing a drug suspended or dissolved therein. The near infrared light in the range from 800 to 1200 nm penetrates a human tissue but is harmless. However, the core material, NIPAAm-AAm, is not completely safe to the tissue of the human body.
In the aforementioned methods, the silica structure enclosing a drug and a reducing agent are allowed to coexist, or a gold-coated fine particulate NIPAAm-AAm is used for the controlled release of the drug. However, the localization of the reducing agent in the diseased portion has technical problems in the method and the safety to be solved.